Didox potentiates the cytotoxic profile of doxorubicin and protects from its cardiotoxicity

Al‐Abd, Ahmed M.; Asaad, Gihan F.; Abdel-Naim, Ashraf B.

doi:10.1016/j.ejphar.2013.08.009

Cited by 22 publications

(18 citation statements)

References 37 publications

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“…DID possesses robust antioxidant activity and potent free radical scavenging capability56. Despite possessing potent antioxidant properties, DID did not antagonize DOX-induced cytotoxicity herein as well as in our previous work against liver cancer cells39. On contrary, DID can be described to possess sensitizing role for DOX-induced cytotoxicity in CRC cells.…”

Section: Discussionmentioning

confidence: 54%

“…In addition, the combination of RES or DID with transtuzumab resulted in synergistic effect in MCF-7 and T47D cells36. Moreover, the combination of DID with DOX showed additive interaction in liver cancer cells39.…”

Section: Discussionmentioning

confidence: 96%

“…It may exert its anti-tumor effect via the activation of various apoptosis pathways35. According to our previous work as well as other research groups, DID and RES improve the cytotoxic profile of different anticancer agents and protect from their toxic effects2836373839.…”

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confidence: 89%

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Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Khaleel

Al‐Abd

Ali

et al. 2016

Sci Rep

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Doxorubicin (DOX) has limited efficacy in colorectal cancer due to multi-drug resistance. Resveratrol (RES) and didox (DID) are polyhydroxyphenols with potential chemosensitizing effects. Herein, we assessed the chemomodulatory effects of RES and DID to DOX in colorectal cancer cells. Equitoxic combination of DOX with RES and DID in HCT 116 reduced the IC50 of DOX from 0.96 ± 0.02 μM to 0.52 ± 0.05 μM and 0.4 ± 0.06 μM, respectively. Similarly, combination of DOX with RES and DID in HT-29 decreased the IC50’s of DOX from 0.88 ± 0.03 μM to 0.47 ± 0.02 μM and 0.29 ± 0.04 μM, respectively. The expressions of p53 and Bax genes were markedly elevated in HCT 116 cells after exposure to DOX/DID. In HT-29 cells, the expression of Bcl-XL gene was significantly decreased after exposure to DOX/DID. In addition, combination of DOX with RES significantly increased the expression of Bax gene in HCT 116 cells. RES treatment induced significant S-phase arrest in DOX-treated HCT 116 cells, while DID induced G2/M- and S-phase arrest in HCT 116 and HT-29, respectively. Both RES and DID significantly enhanced the intracellular entrapment of DOX due to blocking the efflux activity of p-glycoprotein pump. In conclusion, RES and DID sensitize colorectal cancer cells to DOX via facilitating apoptosis and enhancing intracellular entrapment of DOX.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 96%

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Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Khaleel

Al‐Abd

Ali

et al. 2016

Sci Rep

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“…Didox has been shown to inhibit proliferation of several cancer cell types (18)(19)(20)45) and modulate other cancer chemotherapeutic agents resulting in elevated apoptosis (42). Didox was also shown to synergize with temozolomide in brain tumors and with doxorubicin in liver cancer cells (46,47). Our study indicates that combining didox with tamoxifen synergistically reduced cell in RRM2-overexpressing MCF-7, MCF7TamR, and T-47DTamR cells (Fig.…”

Section: Discussionmentioning

confidence: 62%

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Shah

Wilson

Malla

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ERa)-positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through downregulation of ERa66 and upregulation of the 36-kDa variant of ER (ERa36). We identified that NF-kB, HIF1a, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-kB activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired tamoxifen resistance. Because didox also appears to be a potent inhibitor of NF-kB activation, combining didox with tamoxifen treatment cooperatively reverses ER-a alterations and inhibits NF-kB activation. Finally, inhibition of RRM2 by didox reversed tamoxifenresistant in vivo tumor growth and decreased in vitro migratory and invasive properties, revealing a beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance.

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“…Didox is able to inhibit the association of R1 and R2, and thus suppress RNR activity, through its ability to scavenge free radicals and chelate iron [40,41]. Despite its design as an RNR inhibitor, Didox’s free radical scavenger capabilities are important to its broader utility, reducing oxidative stress associated with cardiotoxicity, dementia in HIV patients, and inflammation [13,17,18,42]. …”

Section: Discussionmentioning

confidence: 99%

Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription

McLeod

Caslin

Spence

et al. 2017

Cellular Immunology

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Mast cell activation via the high-affinity IgE receptor (FcεRI) elicits production of inflammatory mediators central to allergic disease. As a synthetic antioxidant and a potent ribonucleotide reductase (RNR) inhibitor, Didox (3,4-dihyroxybenzohydroxamic acid) has been tested in clinical trials for cancer and is an attractive therapeutic for inflammatory disease. We found that Didox treatment of mouse bone marrow-derived mast cells (BMMC) reduced IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF and MIP-1a (CCL3). These effects were consistent using BMMC of different genetic backgrounds and peritoneal mast cells. While the RNR inhibitor hydroxyurea had little or no effect on IgE-mediated function, high concentrations of the antioxidant N-acetylcysteine mimicked Didox-mediated suppression. Furthermore, Didox increased expression of the antioxidant genes superoxide dismutase and catalase, and suppressed DCFH-DA fluorescence, indicating reduced reactive oxygen species production. Didox effects were not due to changes in FcεRI expression or cell viability, suggesting it inhibits signaling required for inflammatory cytokine production. In support of this, we found that Didox reduced FcεRI-mediated AP-1 and NFκB transcriptional activity. Finally, Didox suppressed mast cell-dependent, IgE-mediated passive systemic anaphylaxis in vivo. These data demonstrate the potential use for Didox as a means of antagonizing mast cell responses in allergic disease.

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Didox potentiates the cytotoxic profile of doxorubicin and protects from its cardiotoxicity

Cited by 22 publications

References 37 publications

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Targeting Ribonucleotide Reductase M2 and NF-κB Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription

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